Interleukin-4 receptor cytotoxin as therapy for human malignant pleural mesothelioma xenografts

Ann Thorac Surg. 2004 Aug;78(2):436-43; discussion 436-43. doi: 10.1016/j.athoracsur.2004.03.010.

Abstract

Background: Malignant pleural mesothelioma (MPM) is an uncommon but highly fatal neoplasm for which only limited treatment is available.

Methods: Immunohistochemical analysis was used to determine the expression of interleukin-4 receptors (IL-4R) on mesothelioma cell lines and resected mesothelioma tumors. Radioreceptor binding assays were used to show that these IL-4R were high-affinity receptors. Previously, we had shown that a chimeric protein composed of a circularly permuted IL-4 molecule fused to a truncated form of Pseudomonas exotoxin A, IL-4(38-37)-PE38KDEL, could be used to kill IL-4R-bearing tumor cells in vitro. The toxicity of this molecule to mesothelioma cell lines was tested using a protein synthesis inhibition assay. A human mesothelioma xenograft model was then developed to assess the efficacy of this molecule in vivo.

Results: All MPM cell lines tested were found to express high-affinity cell-surface IL-4R. Immunohistochemical analysis of resected mesothelioma tumor specimens from 13 patients revealed that all tumors expressed moderate-to-high levels of IL-4R. Coculture of malignant mesothelioma cell lines with IL-4(38-37)-PE38KDEL resulted in a dose-dependent inhibition of tumor cell protein synthesis through an interaction with cell-surface IL-4R. In a nude mouse xenograft model of human MPM, intratumoral administration of IL-4(38-37)-PE38KDEL mediated a dose-dependent decrease in tumor volume and a dose-dependent increase in survival.

Conclusions: The chimeric protein, IL-4(38-37)-PE38KDEL, has potent antitumor effects against MPM both in vitro and in vivo.

MeSH terms

  • ADP Ribose Transferases / administration & dosage
  • ADP Ribose Transferases / chemistry
  • ADP Ribose Transferases / therapeutic use*
  • Aged
  • Animals
  • Bacterial Toxins / administration & dosage
  • Bacterial Toxins / chemistry
  • Bacterial Toxins / therapeutic use*
  • Cell Line, Tumor / drug effects
  • Exotoxins / administration & dosage
  • Exotoxins / chemistry
  • Exotoxins / therapeutic use*
  • Female
  • Humans
  • Immunotoxins / therapeutic use*
  • Interleukin-4 / administration & dosage
  • Interleukin-4 / chemistry
  • Male
  • Mesothelioma / chemistry
  • Mesothelioma / drug therapy*
  • Mice
  • Mice, Nude
  • Middle Aged
  • Neoplasm Proteins / analysis
  • Neoplasm Proteins / drug effects*
  • Pleural Neoplasms / chemistry
  • Pleural Neoplasms / drug therapy*
  • Receptors, Interleukin-4 / analysis
  • Receptors, Interleukin-4 / drug effects*
  • Specific Pathogen-Free Organisms
  • Virulence Factors / administration & dosage
  • Virulence Factors / chemistry
  • Virulence Factors / therapeutic use*
  • Xenograft Model Antitumor Assays

Substances

  • Bacterial Toxins
  • Exotoxins
  • Immunotoxins
  • Neoplasm Proteins
  • Receptors, Interleukin-4
  • Virulence Factors
  • interleukin 4 (38-37)-PE38KDEL
  • Interleukin-4
  • ADP Ribose Transferases
  • toxA protein, Pseudomonas aeruginosa